Antibody-mediated mechanisms leading to acute and chronic renal allograft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of appropriate animal models to study the development of allograft injury as the donor-specific antibody (DSA) response is initiated and increases. We have developed a novel model of antibody-mediated rejection (AMR) of renal allografts in CCR5-/- recipients where the titers of DSA elicited in response to complete MHC-mismatched renal allografts are >50-fold higher than those elicited in wild-type recipients. The renal allografts are acutely rejected by this antibody response in CCR5-/- recipients between days 17 and 22 with heavy deposition of C3d, peritubular edema, and neutrophil and macrophage infiltration and activation including production of myeloperoxidase (MPO), histopathologic features of rejection that are characteristic of those observed during AMR in clinical transplants. These and our preliminary results have led us to propose the hypothesis that a key mechanism underlying acute and chronic AMR of renal allografts is the induced infiltration and activation of neutrophils and macrophages in the graft, which directly cause the acute and chronic graft tissue injury and increase the target antigens of the recipient antibody response. This hypothesis will be tested in three specific aims. In Specific Aim 1 we will identify and test the role of MPO-producing cells during antibody-mediated acute rejection of renal allografts in CCR5-/- recipients. In Specific Aim 2 we will test the role of neutrophil and macrophage mediated allograft tissue damage in the generation of donor MHC- and autoantigen-specific antibodies in response to renal allografts. In Specific Aim 3 we will use a B cell depletion strategy to test the molecular mechanisms leading to the development of antibody-mediated interstitital fibrosis and tubular atrophy in the renal allografts. These studies will utilize novel models of antibody-mediated acute and chronic renal allograft injury to provide new insights into mechanisms underlying these pathologies that remain a major problem undermining the success of renal transplantation. We anticipate the results of these studies will indicate new therapeutic targets to inhibit or attenuate antibody-mediated graft injury.